POS0268 INTRAVENOUS TOCILIZUMAB FOR THE TREATMENT OF GIANT CELL ARTERITIS: A PHASE IB DOSE-RANGING PHARMACOKINETIC BRIDGING STUDY
Authors: C. Schmitt, L. Brockwell, M. Giraudon, M. Zucchetto, L. Christ, B. Bannert, T. Daikeler, P. Villiger
Journal: Annals of the Rheumatic Diseases (2022)

Background Subcutaneous (SC) tocilizumab (TCZ), a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody, is approved globally for the treatment of giant cell arteritis (GCA), with once weekly injections, based on the GiACTA trial. Objectives This Phase Ib study ( NCT03923738 ) investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety and exploratory efficacy of 2 doses of TCZ given intravenously (IV) in patients with GCA. The purpose was to explore an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA). Methods This study enrolled patients with GCA in Switzerland who had received ≥5 consecutive doses of TCZ IV 8 mg/kg (off label) Q4W and were in remission. Patients received 5 or 6 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, then received 5 or 6 doses of 6 mg/kg Q4W in period 2. Glucocorticoid use was at the investigator’s discretion. PK endpoints were maximum concentration (C max ), minimum (trough) concentration (C trough ), area under the curve (AUC τ ) over a dosing interval (τ) and average concentration (C mean ) calculated as AUC τ /τ of TCZ after the last dose of each period. Other endpoints included PD markers (IL-6, soluble IL-6R [sIL-6R], C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), safety (adverse events [AEs], serious AEs [SAEs]) and exploratory efficacy (rates of flare and remission). Results In 24 patients enrolled, median (range) age was 65.5 (57-90) years and the majority were female (62.5%). All patients had a history of elevated ESR and/or CRP and evidence of GCA by temporal artery biopsy and/or evidence of large vessel vasculitis at GCA diagnosis. The mean PK profile following TCZ IV 7 mg/kg Q4W in Period 1 was of a similar shape to mean PK profile following TCZ IV 6 mg/kg Q4W in Period 2, with a slightly lower exposure at the 6-mg/kg dose level (Figure 1). Compared with the 7-mg/kg dose, TCZ exposures (C max and AUC τ ) were on average 11.2% and 20.0% lower at the 6-mg/kg dose (Table 1). Mean IL-6 serum concentrations were elevated at baseline due to previous TCZ treatment and remained elevated throughout the study, with slightly higher concentrations in Period 1 (7 mg/kg) than Period 2 (6 mg/kg). Mean sIL-6R concentrations were elevated at baseline and comparable between the 2 doses at steady state. As expected for patients in remission, CRP levels and most ESRs were within the normal ranges at baseline and throughout the study. Overall, 22 patients (91.7%) had ≥1 AE; infections were the most frequently reported AEs. Two patients (8.3%) experienced a Grade ≥3 AE. The majority of AEs (70.8%) were not TCZ-related. Four patients (16.7%) reported an SAE; 1 (pneumococcal pneumonia) was considered TCZ-related by the investigator and 3 led to treatment interruption. There were no deaths. No patients experienced a GCA flare, and all patients remained in remission throughout the study. Table 1. Steady-State PK Parameters of TCZ IV 7 and 6 mg/kg Q4W PK Parameters, mean, median (range) 7 mg/kg IV(Period 1) n=22* 6 mg/kg IV(Period 2) n=22 C max , μg/mL 205 182 197 (118-352) 178 (115-320) AUC τ , day•μg/mL 2150 1720 2130 (1120-4300) 1610 (921-3070) C mean , μg/mL 76.9 61.5 76.0 (40.1-154) 57.5 (32.9-110) C trough , μg/mL 35.3 22.7 37.2 (6.59-69.0) 22.7 (3.38-54.5) AUC τ , area under the curve over a dosing interval (τ); C max , maximum concentration; C mean , mean concentration (AUC τ /τ); C trough , minimum (trough) concentration; IV, intravenous; PK, pharmacokinetics; Q4W, every 4 weeks; TCZ, tocilizumab. *n=21 for C max . Conclusion Both dose levels of TCZ-IV (6 and 7 mg/kg) Q4W were generally well tolerated in patients with GCA. The C max and C mean achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those seen in patients with RA treated with 8 mg/kg IV Q4W, and C trough was within the range observed in patients with GCA treated with once weekly and every 2 weeks SC dosing. Acknowledgements This study was sponsored by F. Hoffmann-La Roche Ltd. Third party medical writing assistance, under the direction of the authors, was provided by Health Interactions, Inc, and was funded by F. Hoffmann-La Roche Ltd. Disclosure of Interests Christophe Schmitt Shareholder of: F. Hoffmann-La Roche Ltd, Employee of: F. Hoffmann-La Roche Ltd, Laura Brockwell Employee of: F. Hoffmann-La Roche Ltd, Mylène Giraudon Employee of: F. Hoffmann-La Roche Ltd, Mauro Zucchetto Employee of: Working for F. Hoffmann-LaRoche Ltd as an employee of Parexel International, Lisa Christ Shareholder of: Gilead Sciences and F. Hoffmann-La Roche Ltd, Consultant of: Bristol-Myers Squibb, Novartis, and Sanofi, Grant/research support from: Gilead Sciences, F. Hoffmann-La Roche Ltd, and Pfizer, Bettina Bannert: None declared, Thomas Daikeler Speakers bureau: Novartis, Consultant of: Advisory fees from Novartis, Grant/research support from: Research support from Novartis, Peter Villiger Speakers bureau: Roche, MSD, AbbVie, Pfizer, Novartis, Grünenthal, Amgen, Sanofi, Chugai, BMS, and Gilead, Consultant of: Advisory fees from Roche, MSD, AbbVie, Pfizer, Novartis, Grünenthal, Amgen, Sanofi, Chugai, BMS, and Gilead, Grant/research support from: Research support from Roche, MSD, AbbVie, and Pfizer